Dana-Farber癌癥研究所的研究人員發(fā)現(xiàn)了一種新的癌癥治療方法,，即通過某種藥物損傷癌細(xì)胞DNA同時(shí)阻止癌細(xì)胞進(jìn)行自我修復(fù)，使癌細(xì)胞自我毀滅從而達(dá)到治療癌癥的目的,。這項(xiàng)研究發(fā)表在8月14日的Molecular Cell雜志上,。
據(jù)研究人員Shapiro介紹，正常細(xì)胞的DNA損傷修復(fù)過程對這類DNA修復(fù)阻斷藥物(repair-blocking drugs)具有較低的敏感性,。這意味著修復(fù)阻斷藥物能夠選擇性阻斷癌細(xì)胞DNA修復(fù),，并對正常細(xì)胞無影響。
機(jī)體對發(fā)生DNA損傷的細(xì)胞有兩種處理方式,。一種為細(xì)胞程序性死亡(programmed cell death),，即凋亡。另一種可以通過檢驗(yàn)點(diǎn)蛋白(checkpoint proteins)發(fā)出的信號(hào)是細(xì)胞進(jìn)入細(xì)胞周期阻滯(cell cycle arrest),。
當(dāng)細(xì)胞的DNA發(fā)生損傷時(shí),，細(xì)胞會(huì)引發(fā)一系列的檢驗(yàn)點(diǎn)級(jí)聯(lián)反應(yīng)（checkpoint cascade）,，cdk1和cdk2這兩種主要的檢驗(yàn)點(diǎn)蛋白,，發(fā)出信號(hào)阻止細(xì)胞周期反應(yīng)，并在DNA損傷位點(diǎn)進(jìn)行DNA修復(fù),。而修復(fù)阻斷藥物的作用是壓制檢驗(yàn)點(diǎn)蛋白發(fā)出的信號(hào),，從而防止化療損傷的癌細(xì)胞進(jìn)行自我修復(fù)。
在臨床試驗(yàn)中,，科學(xué)家利用抑制藥物阻斷cdk信號(hào),。這些藥物能引起損傷細(xì)胞繞過檢驗(yàn)點(diǎn)的控制繼續(xù)生長，分裂和死亡,。研究人員在該研究報(bào)告中還提到了cdk抑制劑作用的分子機(jī)制,。(生物谷Bioon.com)
生物谷推薦原始出處：
Molecular Cell, Volume 35, Issue 3, 327-339, 14 August 2009.doi:10.1016/j.molcel.2009.06.036
Cdk1 Participates in BRCA1-Dependent S Phase Checkpoint Control in Response to DNA Damage
Neil Johnson1,Dongpo Cai1,Richard D. Kennedy2,8,Shailja Pathania3,Mansi Arora4,5,Yu-Chen Li1,Alan D. D'Andrea6,Jeffrey D. Parvin4,5and Geoffrey I. Shapiro1,7,*
1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
2 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
3 Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02115, USA
4 Department of Biomedical Informatics , Ohio State University, Columbus, OH 43210, USA
5 The Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, USA
6 Department of Pediatrics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA
7 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
* Corresponding author
Cdk2 and cdk1 are individually dispensable for cell-cycle progression in cancer cell lines because they are able to compensate for one another. However, shRNA-mediated depletion of cdk1 alone or small molecule cdk1 inhibition abrogated S phase cell-cycle arrest and the phosphorylation of a subset of ATR/ATM targets after DNA damage. Loss of DNA damage-induced checkpoint control was caused by a reduction in formation of BRCA1-containing foci. Mutation of BRCA1 at S1497 and S1189/S1191 resulted in loss of cdk1-mediated phosphorylation and also compromised formation of BRCA1-containing foci. Abrogation of checkpoint control after cdk1depletion or inhibition in non-small-cell lung cancer cells sensitized them to DNA-damaging agents. Conversely, reduced cdk1 activity caused more potent G2/M arrest in nontransformed cells and antagonized the response to subsequent DNA damage. Cdk1 inhibition may therefore selectively sensitize BRCA1-proficient cancer cells to DNA-damaging treatments by disrupting BRCA1 function.
